Studies were conducted to assess the effects of ions, bioresponse modifiers and isoprenylation inhibitors on the stability of intercellular junctions of MDCK cells during Ca++ deprivation. Extracellular calcium was depleted by switching cells to low calcium growth medium and by treatment with chelators in calcium-free buffer. Short chain monocarboxylic acids (MCAs) selectively stabilized "mature" desmosomes in MDCK monolayers during Ca++ deprivation by preventing junctional splitting. Of the bioresponse modifiers tested, KT 5926, a myosin light chain kinase inhibitor and W7, a calmodulin inhibitor, antagonized cell dissociation and rounding by EDTA. Protein kinase inhibitors had little effect on desmosomes under the conditions of our experiments, contrary to one report in the literature which found weak antagonism of desmosome disruption by low calcium medium. Mevinolin, and inhibitor of postconfluent MDCK monolayers by low EDTA concentrations and selectively stabilized desmosomes by inhibiting their internalization. Isoprenylated proteins coprecipitated with anti-desmoplakin antibodies and were present in desmosome-enriched fractions. Studies have begun on the mechanism of action of hepatocyte growth factor (HGF) on the stability of desmosomes and associated structures. Preclinical studies are in progress to assess lovastatin-hydroxysterol combinations for selective cytotoxicity in human tumor cell lines.